JP4397691B2 - Hsp90阻害活性を有するプリン類似体 - Google Patents
Hsp90阻害活性を有するプリン類似体 Download PDFInfo
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- JP4397691B2 JP4397691B2 JP2003540142A JP2003540142A JP4397691B2 JP 4397691 B2 JP4397691 B2 JP 4397691B2 JP 2003540142 A JP2003540142 A JP 2003540142A JP 2003540142 A JP2003540142 A JP 2003540142A JP 4397691 B2 JP4397691 B2 JP 4397691B2
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- compound
- purin
- ylamine
- compounds
- hsp90
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- ZZXKNXMCGBVWEP-UHFFFAOYSA-N n-chloropyrimidin-2-amine Chemical compound ClNC1=NC=CC=N1 ZZXKNXMCGBVWEP-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 108091008569 nuclear steroid hormone receptors Proteins 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002901 organomagnesium compounds Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000013610 patient sample Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 150000008039 phosphoramides Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical class COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- 239000003600 podophyllotoxin derivative Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001855 preneoplastic effect Effects 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000013615 primer Substances 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- CSNFMBGHUOSBFU-UHFFFAOYSA-N pyrimidine-2,4,5-triamine Chemical compound NC1=NC=C(N)C(N)=N1 CSNFMBGHUOSBFU-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000004053 quinones Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000012883 sequential measurement Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 108020003113 steroid hormone receptors Proteins 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical group SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000004950 trifluoroalkyl group Chemical group 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 238000013022 venting Methods 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 150000003752 zinc compounds Chemical class 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/24—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one nitrogen and one sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
Description
(発明の要約)
[式中、Aは、NR1 2、NHSO2R2、NR1NR1 2、NR1OR4、OR3、SR3、所望により置換された低級アルキル、C(O)N(R4)2、グアニジン、アミジン、H、ハロゲン、CN、N3、およびパーハロアルキルから選ばれる;
Xは、炭素数1、炭素数2、または炭素数3の、所望により置換された構造(C1-C3)、またはその他NR1、S、S(O)、S(O)2、0、またはC(O)である;
ここで、炭素数2以上の炭素リンカーについてはこれらはその間に単結合、二重結合、または三重結合を有してよい;
Yは、H、所望により置換されたアルキル、所望により置換されたアルケニル、所望により置換されたアルキニル、所望により置換されたアリール、所望により置換されたアリサイクリック、所望により置換されたアラルキル、所望により置換されたアリールオキシアルキル、所望により置換されたアルコキシアルキル、アルキルアミノアルキル、アルキルカルボニルアミノアルキル(-(CH2)n-C(O)-NR-(CH2)n)、アルキルカルボニルオキシルアルキル(-(CH2)n-C(O)-O-(CH2)n)、所望により置換されたヘテロサイクリック、ヒドロキシアルキル、ハロアルキル、パーハロアルキル、C(O)R2、S(O)2R2、C(O)NHR2、およびC(O)OR2からなる群から選ばれる;
Zは、H、ハロゲン、CN、OR3、SR3、パーハロアルキル、所望により置換されたアルキル、所望により置換されたアルケニル、所望により置換されたアルキニル、所望により置換されたアリール、所望により置換されたアリサイクリック、所望により置換されたアラルキル、所望により置換されたアリールオキシアルキル、所望により置換されたアルコキシアルキル、所望により置換されたヘテロサイクリック、C(O)R2、-S(O)2R2、NHOR4、およびC(O)NR4 2からなる群から選ばれる;
Qは、アルキル、シクロアルキル、アリールアルキル、アリール、ヘテロアリール、およびヘテロサイクリック(すべて所望により置換されている)、例えば、
R1は、独立してH、所望により置換されたアルキル、所望により置換されたシクロアルキル、所望により置換されたヘテロアルキル、所望により置換されたアリール、所望により置換されたヘテロサイクリック、C(O)R2、-C(O)OR2、C()N2、C(S)OR2、C(S)NR4 2、PO3R4、およびSO2R2から選ばれる;
R2は、アルキル、ヘテロアルキル、シクロアルキル、ヘテロサイクリック、ヘテロアリール、およびアリール(すべて所望により置換されている)から選ばれる;
R3は、H、所望により置換されたアルキル、所望により置換されたシクロアルキル、所望により置換されたヘテロアルキル、所望により置換されたアリール、所望により置換されたヘテロサイクリック、およびC(O)NR4 2から選ばれる;
R4は、H、またはアルキル、シクロアルキル、ヘテロアルキル、アリール、およびヘテロサイクリック(すべて所望により置換されている)から選ばれる;
R5は、H、OH、および所望により置換されたアルキルから選ばれる;
R6は、独立してH、所望により置換されたアルキル、OR3、SR3、NHR3、C(O)R5、NO2、CN、ハロゲン、およびS(O)2R2から選ばれる;
いくつかの態様において、アルキル、アルケニル、およびアルキニル置換基は、長さが炭素数1〜8、より好ましくは長さ炭素数1〜6であり、所望により置換されている;
下付き文字「n」は、1〜10(含む)であり、3またはそれ以下が好ましい。]。
(図面の簡単な説明)
(発明の詳細な説明)
定義
用語「カルボキサミド」は、RおよびR'のそれぞれが独立してH、アルキル、アリールおよびアリールアルキルからなる群から選ばれ、アルキル、アリール、およびアリールアルキル基が所望により置換されている
(本発明化合物の合成)
(医薬組成物、投薬、および投与方法)
本発明の方法、化合物、および組成物は、治療する病状に対して特に有用であるように選んだ他のよく知られた治療剤と組み合わせて用いてもよい。例えば、本発明化合物は、知られた抗癌剤および細胞毒性剤と組み合わせると有用かもしれない。さらに、本発明の方法および化合物は、細胞表面増殖因子レセプターと核シグナル開始細胞増殖を結びつけるシグナリング経路の部分の他の阻害剤と組み合わせても有用かもしれない。
(HSP90結合および下流効果を測定するアッセイ)
このように、タンパク質濃度を測定し、細胞内および液体試料中のタンパク質レベルを測定または予測するための、多くの異なるタイプの方法が当該分野で知られている。間接技術には、例えばポリメラーゼ鎖反応(PCR)を用いる核酸ハイブリダイゼーションおよび増幅が含まれる。これら技術は当業者に知られており、例えば、Sambrook、Fritsch & Maniatis、Molecular Cloning: A Laboratory Manual、Second Edition(1989)Cold Spring Harbor Laboratory Press、Cold Spring Harbor、N. Y.、Ausubelら、Current Protocols in Molecular Biology、John Wiley & Sons、NY、1994に記載されており、例えば、米国特許4,699,877、4,918,162、4,968,603、および5,846,749において患者試料中のHer-2/neuの定量、検出、および相対活性に応用されている。用いることができる2つの一般技術の簡単な説明を以下に示す。
実施例1
8-(2,5-ジメトキシベンジル)-N9-ブチルアデニンの合成
工程1. n-BuOH中の5-アミノ-4,6-ジクロロピリミジン(1mmol)の溶液を、80℃でEt3N(1.2mmol)およびn-ブチルアミン(1.0mmol)で処理した。16h後、溶媒を減圧下で除去した。残渣をEtOAcに溶解し、有機層を水で洗浄し、次いで乾燥した(MgSO4)。ろ過し、溶媒を除去して褐色固体の6-クロロ-5-アミノ-4-ブチル ピリミジンを得た。
Rf=0.5、1:1 EtOAc:ヘキサン中;
Rf=0.45、1:1 EtOAc:ヘキサン中;
Rf=0.65、1:1 EtOAc:ヘキサン中;
Rf=0.35、EtOAc中の5% MeOH中;
実施例2
8-(2,5-ジメトキシベンジル)-N9-ペンチニル-2-フルオロアデニンの合成
工程1: 2-(2,5-ジメトキシ-フェニル)-N-(2,5,6-トリアミノ-ピリミジン-4-イル)-アセトアミド,HCl
Rf=0.45、1:3 MeOH:EtOAc中;
Rf=0.65、1:10 MeOH:EtOAc中;
注意:勢いよくガスが放出。水性層をMeOH:CH2Cl2(500ml、1:5)で再抽出した。有機層を濃縮し、2回フラッシュクロマトグラフィで精製(CH2Cl2:EtOAc:ヘキサン:MeOH:Et3N 1500:750:750:50:10 → 1500:750:750:150:10)して、無色粉末の8-(2,5-ジメトキシ-ベンジル)-2-フルオロ-9-ペンタ-4-イニル-9H-プリン-6-イルアミン(4.5g、38%)、2.1を得た。
Rf=0.45、1:1 EtOAc:ヘキサン中;
同様に、2-Cl化合物をHClおよびCuClをHBF4の代わりに用い、工程4に記載の方法と同じように製造した。
実施例3
rt=7.7min;
Rt=7.59;
Rt=7.66;
Rt=8.22;
Rt=8.23;
Rt=9.24;
Rt=7.91;
以下の化合物をこの方法により製造した。
標準的方法により対応するアルコール(NaBH4、MeOH、室温)、トシルヒドラゾン(TsNHNH2、EtOH、還流)、オキシム(RONH2・HCl、DMF、60℃)、アミン(R1R2NH、NaBH(OAc)3、Cl-(CH2)2-Cl、室温)、ホモアリルアルコール(AllSiMe3、TiCl4)、CH2Cl2、-78℃)、またはアルケンを得た。
7.1 2-(6-アミノ-9-ブチル-9H-プリン-8-イルメチル)-4-メトキシ-ベンズアルデヒド
Rt=6.52;
S-リンカー化合物
実施例9
9-ブチル-8-(2-ヨード,5-メトキシ-フェニルスルファニル)-9H-プリン-6-イルアミン
9.6 8-(2-ヨード-5-メトキシ-フェニルスルファニル)-9-(4-メチル-ペンタ-3-エニル)-9H-プリン-6-イルアミン
Rt=9.14min;
9.8 8-(ベンゾチアゾール-2-イルスルファニル)-9-ブチル-9H-プリン-6-イルアミン
Rt=6.53min;
10.1 8-(2,5-ジメトキシ-フェニルスルファニル)-2-アミノ-9(4-メチル-ペンタ-3-エニル)-9H-プリン-6-イルアミン
11.1 8-(2,5-ジメトキシ-フェニルスルファニル)-9H-プリン-6-イルアミン
11.11 8-(2,5-ジメトキシ-フェニルスルファニル)-9-(ペンタ-4-エニル)-9H-プリン-6-イルアミン
12.1 9-ブチル-8-(2-ヨード-5-メトキシ-フェニルスルファニル)-9H-プリン-6-イルアミン
9-ブチル-8-(2-ヨード-5-メトキシ-ベンジル)-9H-プリン-6-イルアミン
Rt=8.45min;
表4
% Her-2分解=(mfi HER-2試料)/(mfi HER-2未処理細胞)x100
表5
* * *
Claims (10)
- Zが、H、Cl、およびFからなる群から選ばれ、
Yが、-(CH2)2CH=C(CH3)2、-(CH2)3CCH、-(CH2)4Br、-(CH2)4Cl、-(CH2)4OAc、-(CH2)4NHEt、-(CH2)4OH、-(CH2)5Br、-(CH2)5Cl、-(CH2)5OAc、および-(CH2)5OHからなる群から選ばれ、
Qが、2,5-ジメトキシフェニル、2-ヨード-5-メトキシフェニル、4-ヨード-5-メトキシフェニル、2-ブロモ-5-メトキシフェニル、および2-クロロ-5-メトキシフェニルからなる群から選ばれる請求項1記載の化合物。 - 請求項1〜3のいずれかに記載の化合物および医薬的に許容される担体または賦形剤を含む医薬組成物。
- 癌を治療するための請求項4記載の医薬組成物。
- 癌が乳癌、メラノーマ、または肺癌からなる群から選ばれる請求項5記載の医薬組成物。
- 炎症、感染性疾患、自己免疫疾患、虚血、繊維形成性疾患、および神経変性を治療するための請求項4記載の医薬組成物。
- HSP90を有する細胞を請求項1に記載の化合物とin vitroで接触させることを含むHSP90を阻害する方法。
- 該細胞が哺乳類細胞である請求項8記載の方法。
- 該哺乳類細胞がヒト由来である請求項9記載の方法。
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WO2003037860A2 (en) | 2003-05-08 |
US20080125446A1 (en) | 2008-05-29 |
JP2005511565A (ja) | 2005-04-28 |
EP2336133A1 (en) | 2011-06-22 |
CA2464031A1 (en) | 2003-05-08 |
AU2002343604C1 (en) | 2009-09-17 |
AU2002343604B2 (en) | 2009-04-09 |
EP1440072A4 (en) | 2005-02-02 |
EP1440072A2 (en) | 2004-07-28 |
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